Halaven · 4.1 Therapeutic indications · 1

HOS-095816 · has-adverse-reaction-information · PDF-Seite 6

Summary of safety profile The most commonly reported adverse reactions related to HALAVEN, are bone marrow suppression manifested as neutropenia, leucopenia, anaemia, thrombocytopenia with associated infections. New onset or worsening of pre-existing peripheral neuropathy has also been reported. Gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, and stomatitis are among reported undesirable effects. Other undesirable effects include fatigue, alopecia, increased liver enzymes, sepsis and musculoskeletal pain syndrome. Tabulated list of adverse reactions Unless otherwise noted, the table shows the incidence rates of adverse reactions observed in breast cancer and soft tissue sarcoma patients who received the recommended dose in Phase 2 and Phase 3 studies. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Where Grade 3 or 4 reactions occurred, the actual total frequency and the frequency of Grade 3 or 4 reactions are given. System Organ Adverse Reactions – all Grades Class Very Common Common Uncommon Rare or not (Frequency %) (Frequency %) (Frequency %) known Infections and Urinary tract Sepsis (0.5%) (G3/4: infestations infection (8.5%) 0.5%)a (G3/4: 0.7%) Neutropenic sepsis Pneumonia (1.6%) (0.2%) (G3/4: 0.2%)a (G3/4: 1.0%) Septic Shock (0.2%) Oral candidiasis (G3/4:0.2%)a Oral herpes Upper respiratory tract infection Nasopharyngitis Rhinitis Herpes zoster * Blood and Neutropenia (53.6%) Lymphopenia (5.7%

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HOS-095812 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - Breast-feeding

HOS-095811 · has-indication-information · PDF-Seite 2

HALAVEN is indicated for the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease (see section 5.1). Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments. HALAVEN is indicated for the treatment of adult patients with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease (see section 5.1).

HOS-095814 · has-interaction-information · PDF-Seite 5

Eribulin is mainly (up to 70%) eliminated through biliary excretion. The transport protein involved in this process is unknown. Eribulin is not a substrate of breast cancer resistance protein (BCRP), organic anion (OAT1, OAT3, OATP1B1, OATP1B3), multi-drug resistance-associated protein (MRP2, MRP4) and bile salt export pump (BSEP) transporters. No drug-drug interactions are expected with CYP3A4 inhibitors and inducers. Eribulin exposure (AUC and Cmax) was unaffected by ketoconazole, a CYP3A4 and P glycoprotein (Pgp) inhibitor, and rifampicin, a CYP3A4 inducer. Effects of eribulin on the pharmacokinetics of other medicines In vitro data indicate that eribulin is a mild inhibitor of the important drug metabolising enzyme CYP3A4. No in vivo data are available. Caution and monitoring for adverse events is recommended with concomitant use of substances that have a narrow therapeutic window and that are eliminated mainly via CYP3A4-mediated metabolism (e.g. alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus). Eribulin does not inhibit the CYP enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 at relevant clinical concentrations. At relevant clinical concentrations, eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3 transporter-mediated activity.

HOS-095815 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are no data from the use of eribulin in pregnant women. Eribulin is embryotoxic, foetotoxic, and teratogenic in rats. HALAVEN should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus. Women of childbearing potential must be advised to avoid becoming pregnant whilst they are receiving HALAVEN and must use highly effective contraception during treatment with HALAVEN and for 7 months after treatment. Men with partners of child-bearing potential should be advised not to father a child while receiving HALAVEN and must use effective contraception during HALAVEN treatment and for 4 months after treatment. Breast-feeding It is unknown whether eribulin/metabolites are excreted in human or animal breast milk. A risk to newborns/infants cannot be excluded and therefore HALAVEN must not be used during breast-feeding (see section 4.3). 5 Fertility Testicular toxicity has been observed in rats and dogs (see section 5.3). Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with HALAVEN.

HOS-095813 · has-warning-information · PDF-Seite 4

Haematology Myelosuppression is dose dependent and primarily manifested as neutropenia (section 4.8). Monitoring of complete blood counts should be performed on all patients prior to each dose of eribulin. Treatment with eribulin should only be initiated in patients with ANC values ≥ 1.5 x 109/l and platelets > 100 x 109/l. Febrile neutropenia occurred in < 5% of patients treated with eribulin. Patients experiencing febrile neutropenia, severe neutropenia or thrombocytopenia, should be treated according to the recommendations in section 4.2. Patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of normal (ULN) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. Although data are limited, patients with bilirubin >1.5 x ULN also have a higher incidence of Grade 4 neutropenia and febrile neutropenia. Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported. Severe neutropenia may be managed by the use of granulocyte colony-stimulating factor (G-CSF) or equivalent at the physician’s discretion in accordance with relevant guidelines (see section 5.1). Peripheral neuropathy Patients should be closely monitored for signs of peripheral motor and sensory neuropathy. The development of severe peripheral neurotoxicity requires a delay or reduction of dose (see section 4.2) In clinical trials, patients with pre-existing neuropathy greater than Grade 2 were excluded. However, patients with pre-existing neuropathy Grade 1 or 2 were no more likely to develop new or worsening symptoms than those who entered the study without the condition. QT prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias or concomitant treatment with medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Hypokalaemia, hypocalcaemia or 4 hypomagnesaemia should be corrected prior to initiating HALAVEN and these electrolytes should be monitored periodically during therapy. Eribulin should be avoided in patients with congenital long QT syndrome. Excipients This medicinal product contains small amounts of eth

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